Diseases and conditions which are alleviated by the inhibition (or “blocking”) of sodium channels, particularly neuronal voltage-gated sodium channels, include acute and chronic pain, particularly neuropathic and inflammatory pain. Persistent (chronic) neuropathic pain occurs in a wide range of clinical conditions, including post-herpetic neuralgia (PHN), trigeminal neuralgia, painful diabetic neuropathy (PDN), lower back pain, post-operative pain, chemotherapy-related and HIV infection. Estimates of the prevalence of chronic neuropathic pain vary greatly by geographical region, ranging from approximately 11% of the population of the U.S. to estimates that 20% of all European adults suffer with moderate to severe chronic pain (see, for example, Hall, G. C. et al., “Primary Care Incidence and Treatment of Four Neuropathic Pain Conditions: A Descriptive Study, 2002-2005,” BMC Fam. Pract. (2008); Vol. 9, No. 26; and Hardt, J. et al., “Prevalence of Chronic Pain in a Representative Sample in the United States,” Pain Medicine (2008), Vol. 9, No. 7, pp. 803-812). In the U.S., the most common chronic neuropathic pain conditions, PHN and PDN, are thought to affect 1 million and 3 million people, respectively (see, for example, Dworkin, R. H. et al., “Advances in Neuropathic Pain Diagnosis, Mechanism, and Treatment Recommendations,” Arch. Neurol. (2003), Vol. 60, pp. 1524-1534).
Numerous pharmacological agents are available for the treatment of neuropathic pain, including tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, anticonvulsants (e.g., gabapentin and pregabalin), local anaesthetics and opioids (e.g., morphine). However, these treatments offer sub-optimal efficacy and/or have unacceptable side effects in a chronic setting, with adequate relief of neuropathic pain reported in only approximately 50% of patients (see, for example, Moulin, D. E., “The Clinical Management of Neuropathic Pain,” Pain Res. Manag. (2006), Vol. 11 (Supplement A), pp. 30A-36A). Frequently, multiple drug therapy with tricyclic antidepressants, anticonvulsants and local anaesthetics is necessary for relief of neuropathic pain.
The Lidoderm® patch (5% lidocaine) belongs to a class of local and topical anaesthetic medications and is approved for the treatment of PHN. However, while lidocaine may have local effects, it is systemically absorbed and must be used with extreme caution when administered topically, as applying to too large a surface area can result in severe systemic toxicity and death.
Voltaren® (diclofenac sodium gel) is a non-steroidal anti-inflammatory agent (NSAID) in a topical formulation. It is a marketed treatment option for osteoarthritis patients. While the risk of gastrointestinal side effects for NSAID topical use is lower than it is for NSAID oral use, these serious side effects remain a concern for topical diclofenac. Furthermore, meaningful elevation of hepatic enzymes has recently been reported in some patients on long-term topical diclofenac, necessitating regular monitoring for hepatotoxicity in this patient population (see, FDA website, MedWatch, 2009; Volteren Gel (diclofenac sodium) 1% topical gel; Safety Labeling Changes Approved by FDA Center for Drug Evaluation and Research—September 2009).
Neuronal voltage-gated sodium channels (Nav's) are well-known to modulate the transmission of pain signals. For example, loss-of-function mutations of Nav1.7, which is expressed primarily in sensory neurons of the peripheral nervous system and is upregulated by both nerve injury and inflammation, cause a human condition known as congenital indifference to pain, which is characterized by an inability to sense pain (see, for example, Goldberg, Y. P. et al., Clin. Genet. (2007), Vol. 71, No. 4, pp. 311-119). Lidocaine and other local anaesthetics act mainly by inhibiting Nav's.
PCT Published Patent Application No. WO 06/110917 is directed to spiro-oxindole compounds which are disclosed as being useful as sodium channel blockers. These compounds, inter alia, inhibit sodium ion flux through sodium channels. As such, the compounds are considered to be sodium channel blockers and are therefore useful for treating diseases and conditions in mammals, preferably humans, which are the result of aberrant voltage-dependent sodium channel biological activity or which may be ameliorated by modulation of the biological activity of sodium channels.
There exists, therefore, a need for a topical pharmaceutical composition comprising a compound that is a sodium channel blocker, preferably a neuronal voltage-gated sodium channel antagonist, for the treatment of pain having minimal systemic exposure of the compound and that is cosmetically and pharmaceutically acceptable for chronic application of the compound to the skin (i.e., non-irritating, non-stinging and non-sensitizing).